Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic lipid exposure is implicated in beta-cell dysfunction in type 2 diabetes. We therefore used oligonucleotide arrays to define global alterations in gene expression in MIN6 cells after 48-h pretreatment with oleate or palmitate. Altogether, 126 genes were altered > or =1.9-fold by palmitate, 62 by oleate, and 46 by both lipids. Importantly, nine of the palmitate-regulated genes are known to be correspondingly changed in models of type 2 diabetes. A tendency toward beta-cell de-differentiation was also apparent with palmitate: pyruvate carboxylase and mitochondrial glycerol 3-phosphate dehydrogenase were downregulated, whereas lactate dehydrogenase and fructose 1,6-bisphosphatases were induced. Increases in the latter (also seen with oleate), along with glucosamine-phosphate N-acetyl transferase, imply upregulation of the hexosamine biosynthesis pathway in palmitate-treated cells. However, palmitate also increased expression of calcyclin and 25-kDa synaptosomal-associated protein (SNAP25), which control distal secretory processes. Consistent with these findings, secretory responses to noncarbohydrate stimuli, especially palmitate itself, were upregulated in palmitate-treated cells (much less so with oleate). Indeed, glucose-stimulated secretion was slightly sensitized by chronic palmitate exposure but inhibited by oleate treatment, whereas both lipids enhanced basal secretion. Oleate and palmitate also induced expression of chemokines (MCP-1 and GRO1 oncogene) and genes of the acute phase response (serum amyloid A3). Increases in transcriptional modulators such as ATF3, CCAAT/enhancer binding protein-beta (C/EBPbeta), C/EBPdelta, and c-fos were also seen. The results highlight links between regulated gene expression and phenotypic alterations in palmitate versus oleate-pretreated beta-cells.
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PMID:Expression profiling of palmitate- and oleate-regulated genes provides novel insights into the effects of chronic lipid exposure on pancreatic beta-cell function. 2194

Monocyte-derived microparticles play an important role in the pathogenesis of diabetic vasculopathy, and angiotensin II receptor blocker and statin have been shown to have a beneficial effect on the angiopathies of hypertension and hyperglycemia in patients with type 2 diabetes mellitus. However, the interaction between angiotensin II receptor blocker and statin, and monocyte-derived microparticles in atherosclerosis is poorly understood. The effects of losartan and simvastatin on circulating concentrations of monocyte-derived microparticles, chemokines, and soluble adhesion markers were studied in hypertensive patients with or without type 2 diabetes mellitus. Monocyte-derived microparticles were measured by flow cytometry, and levels of serum chemokines (MCP-1 and RANTES) and soluble adhesion markers (sP-selectin and sVCAM-1) were measured by enzyme-linked immunosorbent assay. Losartan decreased both the systolic and diastolic blood pressure in hypertensive patients with and without type 2 diabetes mellitus. The concentrations of monocyte-derived microparticles, chemokines, and soluble adhesion molecules were higher in hypertensive patients who also had type 2 diabetes mellitus vs. those who did not. The administration of angiotensin II receptor blocker decreased the circulating concentration of all these markers. In addition, all markers were decreased by combination therapy, and monocyte-derived microparticles were decreased more with combination therapy with losartan and simvastatin than monotherapy with losartan. The administration of angiotensin II receptor blocker inhibited monocyte-derived microparticle generation and suggests that angiotensin II is intimately related to vascular changes that occur in type 2 diabetes mellitus. Combination therapy with a statin and angiotensin II receptor blocker might be valuable as anti-atherosclerotic therapy in patients with type 2 diabetes mellitus and nephropathy.
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PMID:Effects of losartan and simvastatin on monocyte-derived microparticles in hypertensive patients with and without type 2 diabetes mellitus. 1509 33

Atherosclerosis has highly important chronic inflammatory aspects. We investigated anti-inflammatory effects upon initiating insulin therapy by measuring serum high-sensitivity C-reactive protein (hsCRP) and plasma fibrinogen and serum monocyte chemoattractant protein (MCP)-1in patients with poorly controlled type 2 diabetes. In 18 inpatients with type 2 diabetes, we measured serum hsCRP, plasma fibrinogen, serum MCP-1, body weight (BW), girth, and fasting plasma glucose (FPG) before and 2 weeks (14.0 +/- 2.5 days) after initiation of insulin therapy. Daily insulin doses (in units) were approximately 0.2 x BW (in kilograms). Various changes (ratio) were calculated as the ratio of the value during treatment to the pretreatment value. Significant decreases occurred for log(10) hsCRP and FPG (-0.025 +/- 0.557 mg/L, 215 +/- 64.3 mg/dL v -0.213 +/- 0.571 mg/L, 129.8 +/- 32.1 mg/dL; P =.0121, and P =.00002, respectively). This was particularly true for log(10) hsCRP in patients whose BW was unchanged or increased between measurement (P =.0050). There were no significant differences between pretreatment and treatment values for fibrinogen and MCP-1. However, MCP-1 decreased significantly in the group with high-value in the first time point (MCP-1 > 250 pg/mL, n = 9; P =.0224) compared with the low-value group (MCP-1 < 250 pg/mL, n = 9; P =.3164). No significant correlation was found between hsCRP ratio and fibrinogen ratio, MCP-1 ratio, BW ratio, waist girth ratio, or FPG ratio. In conclusion, newly initiated insulin therapy in patients with poorly controlled type 2 diabetes decreased serum hsCRP. The decrease in hsCRP may have resulted largely from anti-inflammatory effects of insulin.
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PMID:Initiation of insulin therapy reduces serum concentrations of high-sensitivity C-reactive protein in patients with type 2 diabetes. 1516 14

We investigated the effects of long-term benidipine treatment on levels of monocyte and endothelial cell activation markers in hypertensive patients with (n = 28) and without (n = 10) type 2 diabetes mellitus. Benidipine, 4 mg/day, was administered for 6 months; there were no other changes in any of the patients pharmacologic regimens during benidipine treatment. Clinical and biochemical data obtained before and after benidipine administration were compared; all markers were measured by ELISA. The levels of platelet activation markers (CD62P, CD63, and PAC-1), microparticles (monocyte-derived microparticles: MDMPs, and endothelial cell-derived microparticles: EDMPs), chemokines (monocyte chemotactic peptide 1: MCP-1, regulated on activation normally T-cell expressed and secreted: RANTES) and soluble adhesion markers (soluble E-selectin and soluble ICAM-1) differed in the control and hypertension groups. In addition, levels of platelet, monocyte, and endothelial cell activation markers, microparticles, chemokines, and soluble adhesion molecules were higher in hypertensive patients than in those without type 2 diabetes. Furthermore, benidipine administration decreased the concentrations of all these markers. The effect of this drug was significant in diabetes patients with high levels of antioxidized low-density lipoprotein (LDL) antibody. These results suggest that benidipine is effective for the treatment of oxLDL-dependent vascular disorders in hypertensive patients with type 2 diabetes.
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PMID:Benidipine improves oxidized LDL-dependent monocyte and endothelial dysfunction in hypertensive patients with type 2 diabetes mellitus. 1582 99

The effect of low-dose atorvastatin on various biomarkers was investigated in patients with type 2 diabetes complicated by hyperlipidemia. At 0 and 12 weeks in both the atorvastatin group (10 mg/d; n=17) and the no-drug group (n=10), high-sensitivity C-reactive protein (hsCRP), monocyte chemoattractant protein (MCP)-1, plasminogen activator inhibitor (PAI)-1, and fibrinogen were measured. At baseline, the entire group of diabetic patients (n=27) had significantly higher values of hsCRP and fibrinogen compared with those in age-matched healthy subjects (n=29): 0.801 (0.306, 1.760) vs 0.282 (0.143, 0.6505) mg/L, P=.0042; 329.1+/-55.0 vs 212.4+/-35.9 mg/dL, P<.0001, respectively. High-sensitivity C-reactive protein decreased significantly with atorvastatin treatment, from 0.801 (0.243, 1.865) to 0.308 (0.200, 0.804) mg/L (P=.0191). Although MCP-1, PAI-1, and fibrinogen did not decrease in the atorvastatin patients overall, the decrease of MCP-1 was significant in women (n=10; from 241.9+/-45.8 to 215.4+/-49.5 pg/mL, P=.0332). No correlation was found between changes in the serum lipid concentrations and changes in hsCRP, MCP-1, PAI-1, or fibrinogen in either the atorvastatin or the no-drug group. In conclusion, low-dose atorvastatin (10 mg/d) significantly decreased hsCRP in patients overall, and MCP-1 was also decreased in women. These findings suggest the possibility that atorvastatin provides an anti-inflammatory effect even at a low dose.
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PMID:The effect of low-dose atorvastatin on circulating monocyte chemoattractant protein-1 in patients with type 2 diabetes complicated by hyperlipidemia. 1612 34

Different degrees of beta-cell failure and apoptosis are present in type 1 and type 2 diabetes. It has been recently suggested that high glucose-induced beta-cell apoptosis in type 2 diabetes shares a final common pathway with type 1 diabetes, involving interleukin-1beta (IL-1beta) production by beta-cells, nuclear factor-kappaB (NF-kappaB) activation, and death via Fas-FasL. The aim of this study was to test whether human islet exposure to high glucose in vitro, or to the type 2 diabetes environment in vivo, induces IL-1beta expression and consequent activation of NF-kappaB-dependent genes. Human islets were isolated from five normoglycemic organ donors. The islets were cultured for 48 h to 7 days at 5.6, 11, or 28 mmol/l glucose. For comparative purposes, islets were also exposed to IL-1beta. Gene mRNA expression levels were assessed by real-time RT-PCR in a blinded fashion. Culture of the human islets at 11 and 28 mmol/l glucose induced a four- to fivefold increase in medium insulin as compared with 5.6 mmol/l glucose, but neither IL-1beta nor IL-1 receptor antagonist (IL-1ra) expression changed. IL-1beta and IL-1ra protein release to the medium was also unchanged. Stimulated human monocytes, studied in parallel, released >50-fold more IL-1beta than the islets. There was also no glucose-induced islet Fas expression. Expression of the NF-kappaB-dependent genes IkappaB-alpha and monocyte chemoattractant protein (MCP)-1 was induced in human islets by IL-1beta but not by high glucose. In a second set of experiments, human islets were isolated from seven type 2 diabetic patients and eight control subjects. The findings on mRNA levels were essentially the same as in the in vitro experiments, namely the in vivo diabetic state did not induce IL-1beta, Fas, or MCP-1 expression in human islets, and also did not modify IL-1ra expression. The present findings suggest that high glucose in vitro, or the diabetic milieu in vivo, does not induce IL-1beta production or NF-kappaB activation in human islets. This makes it unlikely that locally produced IL-1beta is an important mediator of glucotoxicity to human islets and argues against the IL-1beta-NF-kappaB-Fas pathway as a common mediator for beta-cell death in type 1 and type 2 diabetes.
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PMID:Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets? 1624 50

The white adipose tissue, especially of humans, is now recognized as the central player in the mild inflammatory state that is characteristic of obesity. The question is how the increased accumulation of lipid seen in obesity causes an inflammatory state and how this is linked to the hypertension and type 2 diabetes that accompanies obesity. Once it was thought that adipose tissue was primarily a reservoir for excess calories that were stored in the adipocytes as triacylglycerols. In times of caloric deprivation these stored lipids were mobilized as free fatty acids and the insulin resistance of obesity was attributed to free fatty acids. It is now clear that in humans the expansion of adipose tissue seen in obesity results in more blood vessels, more connective tissue fibroblasts, and especially more macrophages. There is an enhanced secretion of some interleukins and inflammatory cytokines in adipose tissue of the obese as well as increased circulating levels of many cytokines. The central theme of this chapter is that human adipose tissue is a potent source of inflammatory interleukins plus other cytokines and that the majority of this release is due to the nonfat cells in the adipose tissue except for leptin and adiponectin that are primarily secreted by adipocytes. Human adipocytes secrete at least as much plasminogen activator inhibitor-1 (PAI-1), MCP-1, interleukin-8 (IL-8), and IL-6 in vitro as they do leptin but the nonfat cells of adipose tissue secrete even more of these proteins. The secretion of leptin, on the other hand, by the nonfat cells is negligible. The amount of serum amyloid A proteins 1 & 2 (SAA 1 & 2), haptoglobin, nerve growth factor (NGF), macrophage migration inhibitory factor (MIF), and PAI-1 secreted by the adipocytes derived from a gram of adipose tissue is 144%, 75%, 72%, 37%, and 23%, respectively, of that by the nonfat cells derived from the same amount of human adipose tissue. However, the release of IL-8, MCP-1, vascular endothelial growth factor (VEGF), TGF-beta1, IL-6, PGE(2), TNF-alpha, cathepsin S, hepatocyte growth factor (HGF), IL-1beta, IL-10, resistin, C-reactive protein (CRP), and interleukin-1 receptor antagonist (IL-1Ra) by adipocytes is less than 12% of that by the nonfat cells present in human adipose tissue. Obesity markedly elevates the total release of TNF-alpha, IL-6, and IL-8 by adipose tissue but only that of TNF-alpha is enhanced in adipocytes. However, on a quantitative basis the vast majority of the TNF-alpha comes from the nonfat cells. Visceral adipose tissue also releases more VEGF, resistin, IL-6, PAI-1, TGF-beta1, IL-8, and IL-10 per gram of tissue than does abdominal subcutaneous adipose tissue. In conclusion, there is an increasing recognition that adipose tissue is an endocrine organ that secretes leptin and adiponectin along with a host of other paracrine and endocrine factors in addition to free fatty acids.
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PMID:Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. 1702 26

It is now recognized that cross-talk between adipocytes and adipose tissue stromal cells such as macrophages contributes to local and systemic inflammation. One factor from adipocytes that may participate in this interaction and that is frequently elevated in inflammatory conditions such as obesity, insulin resistance, and type 2 diabetes is free fatty acids (FFA). To investigate the potential for FFA to enhance macrophage inflammation, we exposed U937 macrophages to physiological levels (150 microM) of FFA. Palmitic acid (PA), the predominant saturated FFA released from adipose tissue, but not unsaturated FFA, induced an approximately 6-fold (p<0.05) increase in IP-10 gene expression (and 2- to 4-fold increases in IL-8, MCP-1, COX-2, and MIG). PA also induced an approximately 2-fold increase (p<0.05) in active NF-kappaB, and two structurally distinct NF-kappaB inhibitors effectively blocked PA-induced IP-10 gene expression. Conditioned medium from PA-treated cells increased lymphocyte migration 41% (p<0.05) which was significantly reduced by IP-10-neutralizing antibody. These results suggest that elevated concentrations of PA commonly present in obese and insulin resistant individuals can increase NF-kappaB-mediated expression of IP-10 in macrophages. These events in turn may lead to an increasing feed-forward loop of chronic inflammation.
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PMID:Palmitic acid induces IP-10 expression in human macrophages via NF-kappaB activation. 1746 67

The aim of this study was to determine whether pitavastatin may prevent the progression of atherosclerotic changes in hyperlipidemic patients. Seventy-five hyperlipidemic patients with and without type 2 diabetes were enrolled to receive pitavastatin 2 mg daily. Cell adhesion molecules (sCD40L, sP-selectin, sE-selectin, and sL-selectin), chemokines (MCP-1 and RANTES) and adiponectin were measured at baseline and after 3 and 6 months of pitavastatin treatment. Adiponectin levels prior to pitavastatin treatment in hyperlipidemic patients with and without diabetes were lower than levels in normolipidemic controls. Both total cholesterol and the LDL-cholesterol (LDL-C) decreased significantly after pitavastatin administration. Additionally, hyperlipidemic patients with type 2 diabetes exhibited a significant increase in adiponectin levels after pitavastatin treatment (before vs. 3 months, 6 months, 2.81+/-0.95 vs. 3.84+/-0.84 microg/ml (p<0.01), 4.61+/-1.15 mug/ml (p<0.001)). Furthermore, hyperlipidemic diabetics exhibited significant decreases in sE-selectin and sL-selectin levels after 6 months of pitavastatin treatment (sE-selectin, before vs. 6 months, 74+/-21 vs. 51+/-10 ng/ml, p<0.05; sL-selectin, before vs. 6 months, 896+/-141 vs. 814+/-129 ng/ml, p<0.05). In addition, adiponectin showed significant correlation with sE-selectin and sL-selectin in diabetic hyperlipidemia. However, MCP-1, RANTES and sCD40L did not exhibit any differences before or after pitavastatin administration. These results suggest that pitavastatin possesses an adiponectin-dependent anti-atherosclerotic effect in hyperlipidemic patients with type 2 diabetes in addition to its lowering effects on total cholesterol and LDL-C.
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PMID:Correlation between adiponectin and reduction of cell adhesion molecules after pitavastatin treatment in hyperlipidemic patients with type 2 diabetes mellitus. 1792 Jun 63

Obesity is characterized by an enhanced infiltration of macrophages to adipose tissues, which is closely associated with the low-grade inflammatory state and obesity-related pathologies such as type 2 diabetes and cardiovascular diseases. We showed here that dehydroabietic acid (DAA) is a potent PPARalpha/gamma dual activator. Furthermore, we examined the anti-inflammatory effects of DAA in stimulated macrophages and in the coculture of macrophages and adipocytes. DAA significantly suppressed the production of proinflammatory mediators such as MCP-1, TNF-alpha, and NO in stimulated RAW 264 macrophages and in the coculture of RAW 264 macrophages and 3T3-L1 adipocytes. These results suggest that DAA is a valuable medicinal and food component for improving inflammatory changes associated with obesity-related diabetes.
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PMID:Dehydroabietic acid, a phytochemical, acts as ligand for PPARs in macrophages and adipocytes to regulate inflammation. 1826 11


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